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Aromatic compound, preparation method and use of aromatic compound

A technology for compounds and mixtures, applied in the field of treatment and/or prevention of depression-related diseases, novel aromatic compounds and their preparation, can solve the problems of poor drugability of compounds, low central nervous system dosage, difficult drugs and the like

Active Publication Date: 2019-10-18
SHANGAI ZHIGEN PHARM & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these drugs also have serious defects: 1. The onset is slow, and it usually takes 2-4 weeks, or even longer, to exert a more obvious curative effect; 2. The treatment response rate is low, and only about 1 / 3 of the patients respond to Response to first treatment drug, but about 2 / 3 of patients respond only after trying multiple antidepressants
At present, the rapid antidepressant mechanism of this compound is still not very clear, it may be due to the stimulation of AMPAR receptors to exert antidepressant effect
[0008] (2R,6R)-HNK has the very desirable feature of rapid onset of action in the treatment of depression, but there are still many shortcomings: such as poor druggability of the compound, unsatisfactory metabolic properties in mice, T 1 / 2 <1h, fast clearance, low plasma exposure, relatively weak antidepressant activity, and low drug distribution into the central nervous system, so it is difficult to directly develop into a drug

Method used

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  • Aromatic compound, preparation method and use of aromatic compound
  • Aromatic compound, preparation method and use of aromatic compound
  • Aromatic compound, preparation method and use of aromatic compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0149] Example 1: Preparation of 2-amino-6-hydroxyl-2-o-tolylcyclohexane-1-one (compound 1)

[0150]

[0151] Step a: Preparation of 1-a

[0152]

[0153] 2-Bromotoluene (13g, 76mmol) was dissolved in dry THF (120mL), protected by Ar, cooled to -90°C with liquid nitrogen ethanol, and n-BuLi (31.92mL, 79.8mmol) was added dropwise for 30 minutes. After stirring at -90°C for 30 min, epoxycyclohexane (8.49 mL, 83.6 mmol) and boron trifluoride ether solution (10.55 mL, 83.6 mmol) were added dropwise, and the mixture was stirred in liquid nitrogen ethanol for 1.5 hours. The reaction was monitored by TLC (EA:PE=1:5), and after the reaction was completed, the saturated NH4Cl solution (100 mL) was used to quench the reaction, and H 2 Diluted with O (150ml), extracted with ethyl acetate (150mL×3), combined the organic phases, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated to remove the low boiling solvent...

Embodiment 2

[0174] Example 2: Preparation of 2-amino-6-hydroxyl-2-m-tolylcyclohexane-1-one (compound 2)

[0175]

[0176] Step a: Preparation of 2-a

[0177]

[0178] Using m-bromotoluene (13.2g, 77.17mmol) and epoxycyclohexane (8.3g, 84.56mmol) as raw materials, prepared according to the method described in step a in Example 1, to obtain 10.95g of yellow oily liquid, yield: 74.6%. 1 H NMR (400MHz, CDCl 3 )δ7.23(t, J=7.4Hz, 1H), 7.06(d, J=7.9Hz, 3H), 3.71–3.60(m, 1H), 2.41(dd, J=12.3, 3.3Hz, 1H), 2.36(d, J=5.3Hz, 3H), 2.12(dd, J=8.1, 3.6Hz, 1H), 1.90–1.81(m, 2H), 1.80–1.72(m, 1H), 1.47–1.30(m, 4H).MS(M+Na) + : 213.1

[0179] Step b: Preparation of 2-b

[0180]

[0181] Using compound 2-a (1.53 g, 8.04 mmol) as raw material, it was prepared according to the method described in step b of Example 1 to obtain 1.33 g of yellow oily liquid, yield: 88.1%. 1 H NMR (400MHz, CDCl 3 )δ7.24(t, J=7.5Hz, 1H), 7.08(d, J=7.4Hz, 1H), 6.95(d, J=7.7Hz, 2H), 3.58(dd, J=12.1, 5.4Hz, 1H),2.56...

Embodiment 3

[0200] Example 3: Preparation of 2-amino-6-hydroxyl-2-m-fluorophenylcyclohexane-1-one (compound 3)

[0201]

[0202] Step a: Preparation of 3-a

[0203]

[0204] Taking m-fluorobromobenzene (9.63g, 55.03mmol) and epoxycyclohexane (5.94g, 60.52mmol) as raw materials, prepared according to the method described in step a in Example 1, to obtain 8.21g of yellow oily liquid, the yield : 76.8%. 1 H NMR (400MHz, CDCl 3 )δ7.32–7.27(m,1H),7.03(d,J=7.5Hz,1H),6.94(dd,J=16.8,9.1Hz,2H),3.64(td,J=9.9,4.2Hz,1H ),2.49–2.38(m,1H),2.12(d,J=8.0Hz,1H),1.86(d,J=10.2Hz,2H),1.77(d,J=12.2Hz,1H),1.48–1.32 (m,4H).MS(M+Na) + :217

[0205] Step b: Preparation of 3-b

[0206]

[0207] Using compound 3-a (1.829 g, 9.42 mmol) as raw material, it was prepared according to the method described in step b of Example 1 to obtain 1.303 g of yellow oily liquid, yield: 72.0%. 1 H NMR (400MHz, CDCl 3 )δ7.32–7.27(m,1H),6.94(ddd,J=18.4,7.3,4.8Hz,2H),6.88–6.83(m,1H),3.61(dd,J=12.1,5.4Hz,1H) ,2.57–2.50...

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Abstract

The invention relates to an aromatic compound, a preparation method and use of the aromatic compound, andspecifically discloses a compound represented by the following formula (I), or a tautomer or anenantiomer or a diastereomer or a racemate of the compound or a mixture of the compound or a pharmaceutically acceptable salt of the compound. The invention further discloses a preparation method ofthe compound and application of the compound in treating nervous systemdiseases.

Description

technical field [0001] The present invention relates to the field of medicines, in particular to a novel aromatic compound, its preparation method and its use as a biologically active substance in medicines in the treatment and / or prevention of depression-related diseases. Background technique [0002] Depression usually refers to mood disorders, which is an affective mental illness characterized by low mood, sadness, despair and depression, accompanied by symptoms such as sleep disturbance, anxiety and physical discomfort, as a common and serious mental illness , seriously affecting the patient's ability to work, quality of life, and even life-threatening. With the aggravation of various stress factors, depression has become a common disease with high incidence in modern society, and its incidence rate is rising rapidly year by year. According to the forecast of the World Health Organization, there are about 300 million people with depression worldwide, and by 2020, it may...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C225/20C07C221/00C07C233/32C07C51/41C07C55/07C07C53/18C07C63/08C07C253/30C07C255/59C07D309/30A61K31/135A61K31/277A61P25/24
CPCC07C225/20C07C233/32C07C55/07C07C53/18C07C63/08C07C255/59C07D309/30A61P25/24C07C2601/14C07B2200/07C07C2601/08C07C2601/18A61K31/135A61K31/277C07C221/00C07C253/30A61K31/122A61K31/133A61P25/00A61P25/04A61P25/28C07C237/02C07D295/145C07D295/155C07C309/04C07C231/14C07C215/44C07C213/08A61K31/351
Inventor 薛涛黄晶王文科陈义朗
Owner SHANGAI ZHIGEN PHARM & TECH CO LTD
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